tbuckley/cabot-search huggingface dataset:
Tuberculosis Diagnoses Following Wildfire Smoke Exposure in California
Authors: Lauren R. Linde, Adam Readhead, Pennan M. Barry, John R. Balmes, Joseph A. Lewnard
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Wildfires are a significant cause of exposure to ambient air pollution in the United States and other settings. Although indoor air pollution is a known contributor to tuberculosis reactivation and progression, it is unclear whether ambient pollution exposures, including wildfire smoke, similarly increase risk. Objectives: To determine whether tuberculosis diagnosis was associated with recent exposure to acute outdoor air pollution events, including those caused by wildfire smoke. Methods: We conducted a case-crossover analysis of 6,238 patients aged ⩾15 years diagnosed with active tuberculosis disease between 2014 and 2019 in 8 California counties. Using geocoded address data, we characterized individuals' daily exposure to <2.5 μm-diameter particulate matter (PM2.5) during counterfactual risk periods 3-6 months before tuberculosis diagnosis (hazard period) and the same time 1 year previously (control period). We compared the frequency of residential PM2.5 exposures exceeding 35 μg/m3 (PM2.5 events) overall and for wildfire-associated and nonwildfire events during individuals' hazard and control periods. Measurements and Main Results: In total, 3,139 patients experienced 1 or more PM2.5 events during the hazard period, including 671 experiencing 1 or more wildfire-associated events. Adjusted odds of tuberculosis diagnosis increased by 5% (95% confidence interval, 3-6%) with each PM2.5 event experienced over the 6-month observation period. Each wildfire-associated PM2.5 event was associated with 23% (19-28%) higher odds of tuberculosis diagnosis in this time window, whereas no association was apparent for nonwildfire-associated events. Conclusions: Residential exposure to wildfire-associated ambient air pollution is associated with an increased risk of active tuberculosis diagnosis.
Lesson of the Week: Insidiously evolving, occult drug interaction involving warfarin and amiodarone
Authors: B Cheung, F M Lam, C R Kumana
Journal: BMJ (1996)

Amiodarone is often prescribed in the treatment of supraventricular, junctional, and ventricular tachycardia, atrial fibrillation, and tachycardias associated with Wolff-Parkinson-White syndrome. Its advantages are its high degree of efficacy and the lack of negative inotropism. However, its use is complicated by its long half life, its side effects—for example, phototoxicity, skin discoloration, neuropathy, hepatitis, thyroid dysfunction, pulmonary fibrosis, and corneal microdeposits—and interactions with other drugs, including warfarin. The interaction between warfarin and amiodarone that results in prolongation of the prothrombin time and a risk of bleeding is well known,1 2 3 and has been attributed to interference with the hepatic degradation of warfarin.4 We report here a patient in whom this interaction was encountered in an apparently paradoxical manner.

Interactions between warfarin and amiodarone may continue after amiodarone has been withdrawn, so more frequent monitoring of the international normalised ratio is advisable

A 72 year old man developed atrial fibrillation after coronary artery bypass graft surgery, and treatment with amiodarone (600 mg daily) was started. A fortnight later he had two transient ischaemic attacks. At that time, 18 …
A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection
Authors: Shahid Husain, Andrew T. Sage, Lorenzo del Sorbo, Marcelo Cypel, Tereza Martinu, Stephen C. Juvet, Andrea Mariscal, Julie Wright, Bonnie T. Chao, Alaa A. Shamandy, S. Hossein Mousavi, Jin Ma, Bo Wang, Jerome Valero, Mingyao Liu, Megan Landes, Sharaniyaa Balachandran, Kimberley Hudson, Michelle Ngai, Marialessia Capuano, Maria Gelardi, Enrico Lupia, Daniel R. Marinowic, Frederico O. Friedrich, Carine R.R. Schmitz, Leticya S.M. dos Santos, Florencia M. Barbe-Tuana, Marcus H. Jones, Kevin C. Kain, Tony Mazzulli, Sam Sabbah, Shaf Keshavjee
Journal: European Respiratory Journal (2022)

Patients who present to an emergency department (ED) with respiratory symptoms are often conservatively triaged in favour of hospitalisation. We sought to determine if an inflammatory biomarker panel that identifies the host response better predicts hospitalisation in order to improve the precision of clinical decision making in the ED.From April 2020 to March 2021, plasma samples of 641 patients with symptoms of respiratory illness were collected from EDs in an international multicentre study: Canada (n=310), Italy (n=131) and Brazil (n=200). Patients were followed prospectively for 28 days. Subgroup analysis was conducted on confirmed coronavirus disease 2019 (COVID-19) patients (n=245). An inflammatory profile was determined using a rapid, 50-min, biomarker panel (RALI-Dx (Rapid Acute Lung Injury Diagnostic)), which measures interleukin (IL)-6, IL-8, IL-10, soluble tumour necrosis factor receptor 1 (sTNFR1) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1).RALI-Dx biomarkers were significantly elevated in patients who required hospitalisation across all three sites. A machine learning algorithm that was applied to predict hospitalisation using RALI-Dx biomarkers had a mean±sd area under the receiver operating characteristic curve of 76±6% (Canada), 84±4% (Italy) and 86±3% (Brazil). Model performance was 82±3% for COVID-19 patients and 87±7% for patients with a confirmed pneumonia diagnosis.The rapid diagnostic biomarker panel accurately identified the need for inpatient care in patients presenting with respiratory symptoms, including COVID-19. The RALI-Dx test is broadly and easily applicable across many jurisdictions, and represents an important diagnostic adjunct to advance ED decision-making protocols.
Transcriptomic clustering of critically ill COVID-19 patients
Authors: Cecilia López-Martínez, Paula Martín-Vicente, Juan Gómez de Oña, Inés López-Alonso, Helena Gil-Peña, Elías Cuesta-Llavona, Margarita Fernández-Rodríguez, Irene Crespo, Estefanía Salgado del Riego, Raquel Rodríguez-García, Diego Parra, Javier Fernández, Javier Rodríguez-Carrio, Francisco José Jimeno-Demuth, Alberto Dávalos, Luis A. Chapado, Eliecer Coto, Guillermo M. Albaiceta, Laura Amado-Rodríguez
Journal: European Respiratory Journal (2022)

Background Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a severe disease, termed coronavirus disease 2019 (COVID-19), with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms and their modulation has shown a mortality benefit. Methods In a cohort of 56 critically ill COVID-19 patients, peripheral blood transcriptomes were obtained at admission to an intensive care unit (ICU) and clustered using an unsupervised algorithm. Differences in gene expression, circulating microRNAs (c-miRNAs) and clinical data between clusters were assessed, and circulating cell populations estimated from sequencing data. A transcriptomic signature was defined and applied to an external cohort to validate the findings. Results We identified two transcriptomic clusters characterised by expression of either interferon-related or immune checkpoint genes, respectively. Steroids have cluster-specific effects, decreasing lymphocyte activation in the former but promoting B-cell activation in the latter. These profiles have different ICU outcomes, despite no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in two external validation cohorts (with 50 and 60 patients), yielding similar results. Conclusions These results reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19 with the aim to ultimately personalise their therapies.
Reply
Authors: Pallavi Subramanian, Sofia Gargani, Dimitris L. Kontoyiannis, Triantafyllos Chavakis
Journal: Hepatology (2022)

We appreciate the interest of the author of the letter for our work. We disagree with this author's comment "that the conclusions made in the paper cannot be supported by the data." The technical concerns raised neither invalidate our methodological and experimental approach nor counteract the conclusion of our study that human antigen R (HuR) protects against NAFLD. In fact, our study's conclusion is fully supported by a recent preprint manuscript.1 Regarding the concerns, we reply the following: The Albumin‐Cre (Alb‐Cre) transgene is commonly used for hepatocyte‐specific recombination of loxP‐flanked alleles. Although this driver may recombine in cholangiocytes, we used the term "hepatocyte‐specific HuR knockout," as our analyses2 focused on hepatocytes, by far the most abundant cells in the liver. We think that the suggested term "liver‐specific HuR knockout" is misleading, as HuR is not deleted in all liver cells (e.g., stellate cells and Kupffer cells) using the Alb‐Cre transgene. The recombination induced by Alb‐Cre has been considered as hepatocyte‐specific also by others in the literature (references Singh et al.3 and Dall et al.4 to cite a few out of many). Our flow cytometry analysis2 was not intended to categorize in detail the cell subsets involved in liver inflammation but to assess differences in inflammatory cell accumulation between HuR‐deficient and HuR‐sufficient mice fed a choline deficient high‐fat diet with 45 kcal% fat (CD‐HFD‐45%). To this end, we did not use cluster of differentiation 45 (CD45) staining but rather relied on Percoll‐enriched leukocyte fractions and FSC/SSC size gating. The CD4, CD8, and NK1.1 markers were used for the gross assessment of lymphocytes. Although we appreciate that a complete distinction of NKT (natural killer T) cells from NK (natural killer) cells requires further markers, we considered these cells as NKT cells based on an important article demonstrating that NKT cells are an NK1.1+ population strongly increasing in CD‐HFD‐45%–fed mice.5 In the Results, we unequivocally indicate that our measurements reflect CD4−CD8−NK1.1+ cell counts. The comment on the MHC‐II (major histocompatibility complex‐II) and CD8 antibodies with the same fluorophore relies likely on an oversight of the author of the letter, as these antibodies were used in distinct analyses involving separate aliquots (different Figure S4 panels). Fc blockade is always used in our stainings (without it, it would have been impossible to distinguish immune cell subsets). Given the brevity of technical description of established routine procedures, we omitted this standard procedure. Together, the technical concerns raised have not compromised our approach and our conclusion on HuR's protective role in NAFLD.
Pre-pubertal smoke exposure of fathers and increased risk of offspring asthma: a possible transgenerational effect
Authors: Jiacheng Liu, Gayan Bowatte, Jonathan Pham, Jennifer L. Perret, John W. Holloway, Adrian J. Lowe, John A. Burgess, Cecilie Svanes, Paul Thomas, Melissa A. Russell, Bircan Erbas, Caroline J. Lodge, David Martino, Gita D. Mishra, Michael J. Abramson, Eugene H. Walters, Shyamali C. Dharmage, Dinh S. Bui
Journal: European Respiratory Journal (2022)

Asthma is a major non-communicable disease in children [1]. Pre- and post-natal exposure to tobacco smoke are major risk factors for childhood asthma [1, 2]. While there is evidence that mothers' intrauterine exposure to second-hand smoke is associated with asthma in the offspring [3, 4], there is also increasing concern that fathers who start smoking before completing puberty may elevate the risk of asthma in their offspring [4, 5]. The suggestion is that this may be as a result of epigenetic changes to sperm precursor (stem) cells during gonadal maturation [4, 5]. However, this is rather speculative, and as yet little is actually known about whether fathers' passive smoke exposure throughout childhood to puberty is indeed associated with increased asthma risk in their offspring. The risk of non-allergic childhood asthma in offspring may increase if their fathers were exposed to pre-pubertal passive smoke <https://bit.ly/3bMHZnP> This study is based on the data collected within the Tasmanian Longitudinal Health Study (TAHS). The authors gratefully acknowledge all the participants and research staff of the TAHS.
Incidence, risk factors, and final causes for misdiagnosis of tuberculosis in the Republic of Korea: a population-based longitudinal analysis
Authors: Changwhan Kim, Yousang Ko, Jin-Wook Moon, Yong-Bum Park, So Young Park, Ga-Young Ban, Ju Yeun Song, Hajeong Kim, Yun Su Sim, Ji Young Park, Chang Youl Lee
Journal: European Respiratory Journal (2022)

<b>Misdiagnosis of TB was 7.3% and the trend was unchanged in the 2010s, despite a remarkable decline of TB incidence in the ROK. Misdiagnosis was more common in EPTB than PTB, and risk factors and final causes varied depending on each involved organ system.</b>https://bit.ly/3qnLjJN
Narrative review to capture patients’ perceptions and opinions about non-response and response to biological therapy for severe asthma
Authors: Courtney Coleman, Ekaterina Khaleva, Anna Rattu, Betty Frankemölle, Hanna Nielsen, Graham Roberts, Clare Williams
Journal: European Respiratory Journal (2022)

Background There are now many biological therapies to treat severe asthma. To assess which work best for which patient, we need to develop definitions of response. This narrative review aims to capture severe asthma patients’ perceptions about non-response and response to biological therapy. Methods Four bibliographic databases were searched from inception to September 2021. Grey literature was searched with the involvement of patient representatives. A thematic approach was used for synthesis. No qualitative studies specifically explore patients’ perspectives on response to biological therapy for severe asthma. Three papers and one published asthma patient interview were included. Relevant grey literature was included from online discussion forums, blogs and social media websites. Results Adult patients framed positive response to biological therapy in terms of reduced burden of disease and treatment. Both were multifaceted. Some patients experienced reduced benefit from biological therapy over time. There was a group of patients who described a limited response or non-response to biological therapy. This was framed within the context of continuing hospitalisation and oral corticosteroid treatment. The speed of onset of benefit was felt to be important by some. Conclusions Definitions of non-response and response need to be patient-centred, yet there is a complete lack of qualitative research focused on this topic. By combining relevant published and grey literature we have provided a description of adult patients’ perceptions of response to biological therapy in severe asthma. We now need to understand the views of children and adolescents with severe asthma and their carers, and diverse patient experiences in real-world settings.
Association of obstructive sleep apnoea with cardiovascular events in women and men with acute coronary syndrome
Authors: Xiao Wang, Jingyao Fan, Ruifeng Guo, Wen Hao, Wei Gong, Yan Yan, Wen Zheng, Hui Ai, Bin Que, Dan Hu, Changsheng Ma, Xinliang Ma, Virend K. Somers, Shaoping Nie
Journal: European Respiratory Journal (2022)

The impact of sex on the association of obstructive sleep apnoea (OSA) with recurrent cardiovascular events following acute coronary syndrome (ACS) remains uncertain. This study sought to examine the association between OSA and long-term cardiovascular outcomes in women and men with ACS.In this prospective cohort study, we recruited 2160 ACS patients undergoing portable sleep monitoring between June 2015 and January 2020. The primary end-point was major adverse cardiovascular and cerebrovascular event (MACCE), including cardiovascular death, myocardial infarction, stroke, ischaemia-driven revascularisation or hospitalisation for unstable angina or heart failure.After exclusion of patients with failed sleep studies, central sleep apnoea, regular continuous positive airway pressure therapy and loss of follow-up, 1927 patients were enrolled. Among them, 298 (15.5%) were women and 1014 (52.6%) had OSA (apnoea-hypopnoea index ≥15 events·h-1). The prevalence of OSA was 43.0% and 54.4% in women and men, respectively. In 4339 person-years (median 2.9 years, interquartile range 1.5-3.6 years), the cumulative incidence of MACCE was significantly higher in OSA versus non-OSA groups in the overall population (22.4% versus 17.7%; adjusted hazard ratio (HR) 1.29, 95% CI 1.04-1.59; p=0.018). OSA was associated with greater risk of MACCE in women (28.1% versus 18.8%; adjusted HR 1.68, 95% CI 1.02-2.78; p=0.042), but not in men (21.6% versus 17.5%; adjusted HR 1.22, 95% CI 0.96-1.54; p=0.10). No significant interaction was noted between sex and OSA for MACCE (interaction p=0.32). The incremental risk in women was attributable to higher rates of hospitalisation for unstable angina and ischaemia-driven revascularisation.In hospitalised ACS patients, OSA was associated with increased risk of subsequent events, particularly among women. Female patients with ACS should not be neglected for OSA screening and dedicated intervention studies focusing on women with ACS and comorbid OSA should be prioritised.
A 30-Year Follow-Up of the Dallas Bed Rest and Training Study
Authors: Darren K. McGuire, Benjamin D. Levine, Jon W. Williamson, Peter G. Snell, C. Gunnar Blomqvist, Bengt Saltin, Jere H. Mitchell
Journal: Circulation (2001)

Background — Cardiovascular capacity declines with aging, as evidenced by declining maximal oxygen uptake (V̇ o 2 max ), with little known about the specific mechanisms of this decline. Our study objective was to assess the effect of a 30-year interval on body composition and cardiovascular response to acute exercise in 5 healthy subjects originally evaluated in 1966. Methods and Results — Anthropometric parameters and the cardiovascular response to acute maximal exercise were assessed with noninvasive techniques. On average, body weight increased 25% (77 versus 100 kg) and percent body fat increased 100% (14% versus 28%), with little change in fat-free mass (66 versus 72 kg). On average, V̇ o 2 max decreased 11% (3.30 versus 2.90 L/min). Likewise, V̇ o 2 max decreased when indexed to total body mass (43 versus 31 mL · kg −1 · min −1 ) or fat-free mass (50 versus 43 mL/kg fat-free mass per minute). Maximal heart rate declined 6% (193 versus 181 bpm) and maximal stroke volume increased 16% (104 versus 121 mL), with no difference observed in maximal cardiac output (20.0 versus 21.4 L/min). Maximal AV oxygen difference declined 15% (16.2 versus 13.8 vol%) and accounted for the entire decrease in cardiovascular capacity. Conclusions — Cardiovascular capacity declined over the 30-year study interval in these 5 middle-aged men primarily because of an impaired efficiency of maximal peripheral oxygen extraction. Maximal cardiac output was maintained with a decline in maximal heart rate compensated for by an increased maximal stroke volume. Most notably, 3 weeks of bedrest in these same men at 20 years of age (1966) had a more profound impact on physical work capacity than did 3 decades of aging.
Loss of liver function in chronic liver disease: An identity crisis
Authors: Carmen Berasain, Maria Arechederra, Josepmaria Argemí, Maite G. Fernández-Barrena, Matías A. Avila
Journal: Journal of Hepatology (2022)

Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can occur as part of the regenerative mechanisms triggered in response to acute liver injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core transcription factors and splicing regulators that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, is of high clinical relevance. In this context, we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4α, whose impairment mediates the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core transcription factor expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate structural abnormalities. The possibility of correcting the phenotype of severely damaged and malfunctional livers may reveal new therapeutic opportunities for individuals with cirrhosis and advanced liver disease.
Multi-Omics Data Reveal the Effect of Sodium Butyrate on Gene Expression and Protein Modification in <i>Streptomyces</i>
Authors: Jiazhen Zheng, Yue Li, Ning Liu, Jihui Zhang, Shuangjiang Liu, Huarong Tan
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Streptomycetes possess numerous gene clusters and the potential to produce a large amount of natural products. Histone deacetylase (HDAC) inhibitors play an important role in the regulation of histone modifications in fungi, but their roles in prokaryotes remain poorly understood. Here, we investigated the global effects of the HDAC inhibitor, sodium butyrate (SB), on marine-derived Streptomycesolivaceus FXJ 8.021, particularly focusing on the activation of secondary metabolite biosynthesis. The antiSMASH analysis revealed 33 secondary metabolite biosynthetic gene clusters (BGCs) in strain FXJ 8.021, among which the silent lobophorin BGC was activated by SB. Transcriptomic data showed that the expression of genes involved in lobophorin biosynthesis (ge00097–ge00139) and CoA-ester formation (e.g., ge02824), as well as the glycolysis/gluconeogenesis pathway (e.g., ge01661), was significantly up-regulated in the presence of SB. Intracellular CoA-ester analysis confirmed that SB triggered the biosynthesis of CoA-ester, thereby increasing the precursor supply for lobophorin biosynthesis. Further acetylomic analysis revealed that the acetylation levels on 218 sites of 190 proteins were up-regulated and those on 411 sites of 310 proteins were down-regulated. These acetylated proteins were particularly enriched in transcriptional and translational machinery components (e.g., elongation factor GE04399), and their correlations with the proteins involved in lobophorin biosynthesis were established by protein–protein interaction network analysis, suggesting that SB might function via a complex hierarchical regulation to activate the expression of lobophorin BGC. These findings provide solid evidence that acetylated proteins triggered by SB could affect the expression of genes involved in the biosynthesis of primary and secondary metabolites in prokaryotes.
Selected Articles from This Issue
Journal: Clinical Cancer Research (2022)

Previous treatment strategies for medulloblastoma have shown moderate improvement in response.However, the long-term overall survival remains disappointing, and many survivors have profound long-term complications.Therefore, there is a tremendous need to develop novel, improved, and safer therapeutic strategies for medulloblastoma.The critical tumor-stroma interactions mediated by the PlGF/NRP1 pathway make it an attractive target.Sholler and colleagues report a phase I, open-label, multicenter, dose-escalation study of the anti-PlGF antibody, TB-403, in pediatric subjects.TB-403 treatment was well tolerated and induced stable disease in high-risk, heavily pretreated relapsed medulloblastoma allowing for excellent quality of life.These findings indicate that treatment with TB-403 may represent a potentially transformative therapy for children with medulloblastoma and should be tested in larger studies.